(1) Field of the Invention
The present invention relates to a process for producing 2-substituted propionic acid having effects as anti-inflammatory agent, analgesic, antipyretic and so forth.
(2) Prior Art
As disclosed in Japanese Patent Publication No. S58-004699, compounds of 2-substituted propionic acid have effects as anti-inflammatory agent, analgesic and antipyretic. Especially, 2-[4-(2-oxocyclopentan-1-yl methyl)phenyl]propionic acid, xe2x80x9cloxoprofenxe2x80x9d, is commercially available as an excellent analgesic drug.
In addition to the above disclosure, as disclosed in Japanese Laid-Open Patent Publication No. S62-161740, the conventional preparation process includes the steps of (1) coupling reaction of 2-(p-halomethylphenyl)propionic acid ester with 2-cyclopentanone carboxylic acid ester in the presence of a base, and (2) decarboxylation and hydrolysis of ester with an acid.
In the above first coupling step, the hydrogen atom at xcex1-position of 2-cyclopentanone carboxylic acid ester, is taken off to give 2-(alkoxycarbonyl)-cyclopentenolate anion, which attacks the halomethyl group of 2-(p-halomethylphenyl)propionic acid ester to generate carbon-carbon bond so that the fundamental skeletal structure of loxoprofen is formed.
Although above 2-(p-halomethylphenyl)propionic acid ester is relatively inexpensive, 2-cyclopentanone carboxylic acid ester is an expensive reagent.
Furthermore, the reaction in the presence of a base, the base likely causes side reaction with halomethyl group of 2-(p-halomethylphenyl)propionic acid ester.
Proposed in PCT International Publication No. WO 97/47581 is a method that loxoprofen is produced through carbonylation of p-chloromethylstyrene in the presence of a transition metal complex catalyst. That is, the method comprises (i) carbonylation of p-chloromethylstyrene, (ii) coupling with cyclopentanone carboxylic acid ester, and (iii) decarboxylation and hydrolysis.
The above method of utilizing carbonylation is advantageous in industrial working because the structure of substituted styrene can easily be converted into the structure of substituted propionic acid ester.
However, p-chloromethylstyrene has a high polymerization activity in the presence of heat, light and pressure owing to the existence of substituted chloromethyl groups bonded to the benzene ring. Particularly in the carbonylation with a transition metal complex catalyst, p-chloromethylstyrene is liable to polymerize. This fact may be apprehended in view of the fact that commercially available p-chloromethylstyrene usually contains polymerization inhibitor and that polymerization inhibitor may be added in carbonylation as described on page 6 of the foregoing International Publication.
As described above, p-chloromethylstyrene is liable to cause self-polymerization, so that, according to the above International Publication, polymerization inhibitor is added during the carbonylation as above. In addition, it is required to use solvents as much as several times to several tens times, mostly over ten times the volume of p-chloromethylstyrene as substrate in all the examples on carbonylation.
However, the necessity for large quantity of solvent relative to the substrate substance of p-chloromethylstyrene is not advantageous in industrial practice.
In the method as described in the above International Publication, highly reactive vinyl groups are reacted to convert into other less reactive substituents in the first step among plurality of steps. This method cannot always be regarded as reasonable in industrial scale process in view of the fact that the high reactivity of vinyl group is not taken into consideration sufficiently.
Moreover, the method disclosed in the above International Publication cannot be said as inexpensive because expensive cyclopentanone carboxylic acid alkyl ester is used as a starting material. In addition, the yield is not always satisfactory either.
As mentioned above, the most suitable method for producing loxoprofen has not yet been proposed, and a more efficient method is wanted.
It is the object of the present invention to provide a process for producing loxoprofen using adipic acid diester as one of starting materials, which is more effective as compared with conventional methods.
More particularly, a first aspect of the present invention relates to a process for producing a compound as represented by the following general formula II (hereinafter referred to as xe2x80x9ccompound IIxe2x80x9d): 
wherein Rxe2x80x2 represents an alkyl group having 4 or less carbon atoms, Rxe2x80x3 represents hydrogen atom or an alkyl group having 4 or less carbon atoms, and Rxe2x80x2 and Rxe2x80x3 can be either the same or different,
which process comprises the steps of:
to cause adipic acid diester to react with alkoxide as represented by the following general formula:
M(OR)n
wherein R represents an alkyl group having 5 or less carbon atoms, M represents alkali metal or alkaline earth metal, n represents the number corresponding to the valence of M and (OR)""s of n in number can be either the same or different,
to subject successively the above product to coupling with halomethylstyrene to obtain the compound as represented by the following general formula I (hereinafter referred to as xe2x80x9ccompound Ixe2x80x9d): 
wherein Rxe2x80x2 represents an alkyl group having 4 or less carbon atoms,
and to cause the above compound I to react with carbon monoxide and water or alcohol in the presence of a metal catalyst to obtain the above compound II.
A second aspect of the present invention relates to a process for producing 2-substituted propionic acid as represented by the following general formula III (hereinafter referred to as xe2x80x9ccompound IIIxe2x80x9d): 
which process comprises the steps of (1-1) to (1-3):
step (1-1) to cause adipic acid diester to react with alkoxide as represented by the following general formula:
M(OR)n
wherein R represents an alkyl group having 5 or less carbon atoms, M represents alkali metal or alkaline earth metal, n represents the number corresponding to the valence of M, and (OR)""s of n in number can be either the same or different, and successively subjecting the above product to coupling with halomethylstyrene to obtain the compound I as represented by the following general formula I: 
wherein Rxe2x80x2 represents an alkyl group having 4 or less carbon atoms,
step (1-2) to cause the above compound I to react with carbon monoxide and water or alcohol in the presence of metal catalyst to obtain a compound II as represented by the following general formula II: 
wherein Rxe2x80x2 represents an alkyl group having 4 or less carbon atoms, Rxe2x80x3 represents hydrogen atom or an alkyl group having 4 or less carbon atoms, and Rxe2x80x2 and Rxe2x80x3 can be either the same or different, and
step (1-3) to subject the above compound II to decarboxylation and hydrolysis to obtain the above compound III.
A third aspect of the present invention relates to a process for the production as described in the first or second aspect, wherein halomethylstyrene is chloromethylstyrene.
According to the above methods, the halomethyl group of halomethylstyrene is converted into a particular substituent, so that the liability for self-polymerization of vinyl group is reduced. Therefore, a large quantity of solvent is not required in carbonylation. Furthermore, it is possible to produce 2-substituted propionic acid effectively using an inexpensive starting material.
A fourth aspect of the present invention relates to a process for producing a compound II as represented by the following general formula II: 
wherein Rxe2x80x2 represents an alkyl group having 4 or less carbon atoms, Rxe2x80x3 represents hydrogen atom or an alkyl group having 4 or less carbon atoms, and Rxe2x80x2 and Rxe2x80x3 can be either the same or different,
which process comprises the steps of:
causing adipic acid diester to react with alkoxide as represented by the following general formula:
M(OR)n
wherein R represents an alkyl group having 5 or less carbon atoms, M represents alkali metal or alkaline earth metal, n represents the number corresponding to the valence of M, and (OR)""s of n in number can be either the same or different,
successively subjecting the product obtained above to coupling with a compound as represented by the following general formula IV (hereinafter referred to as xe2x80x9ccompound IVxe2x80x9d) to obtain the above compound II, 
wherein X represents halogen atom, and Rxe2x80x3 represents hydrogen atom or an alkyl group having 4 or less carbon atoms.
A fifth aspect of the present invention relates to a process for producing 2-substituted propionic acid as represented by the following formula III (compound III): 
which process comprises the steps of (2-1) and (2-2):
step (2-1) to cause adipic acid diester to react with alkoxide as represented by the following general formula:
M(OR)n
wherein R represents an alkyl group having 5 or less carbon atoms, M represents alkali metal or alkaline earth metal, n represents the number corresponding to the valence of M, and (OR)""s of n in number can be either the same or different,
and successively subjecting the product obtained above to coupling with a compound IV as represented by the following general formula IV to obtain a compound II as represented by the general formula II: 
wherein X represents halogen atom, and Rxe2x80x3 represents hydrogen atom or an alkyl group having 4 or less carbon atoms, and 
wherein Rxe2x80x2 represents an alkyl group having 4 or less carbon atoms, Rxe2x80x3 represents hydrogen atom or an alkyl group having 4 or less carbon atoms, and Rxe2x80x2 and Rxe2x80x3 can be either the same or different,
step (2-2) to subject the above compound II to decarboxylation and hydrolysis to obtain the above compound III.
A sixth aspect of the present invention relates to a process for the production as described in the fourth or fifth aspect, wherein halogen atom X in the general formula IV is chlorine or bromine.
A seventh aspect of the present invention relates to a process for the production as described in any one of fourth to sixth aspects, wherein Rxe2x80x3 in the general formula IV is hydrogen atom, or methyl or ethyl group.
An eighth aspect of the present invention relates to a production process as described in any one of first to seventh aspects, wherein the effective amount of alkoxide, M(OR)n, is 0.7 to 1 equivalent relative to 1 mole of adipic acid diester during the reaction.
A ninth aspect of the present invention relates to a production process as described in any one of first to eighth aspects, wherein adipic acid diester is dimethyl adipate or diethyl adipate.
A tenth aspect of the present invention relates to a production process as described in any of first to ninth aspects, wherein alkoxide, M(OR)n, is sodium methoxide or sodium ethoxide.
In all the processes for production according to the present invention, adipic acid diester is used as a starting material. One process comprises the step (1-1): [coupling], step (1-2): [carbonylation] and step (1-3): [decarboxylation and hydrolysis]. The other process comprises the step (2-1): [coupling] and step (2-2) [decarboxylation and hydrolysis].
In the first place, the production process comprising steps of (1-1) to (1-3) will be described in the order of steps.
Step (1-1): [Coupling]
In step (1-1), after Dieckmann condensation of dimethyl adipate with the above alkoxide M(OR)n, is carried out to produce 2-(alkoxycarbonyl)cyclopentenolate anion, the above obtained compound is successively subjected to the coupling with halomethylstyrene to obtain a compound I.
In the present step, 2-(alkoxycarbonyl)cyclopentenolate anion is produced as an intermediate product, which is then subjected to coupling with halomethylstyrene without isolation. Although both the compounds are unsaturated ones, it is advantageous because the carbon-carbon double bonds in halomethylstyrene are almost inactive in this reaction. Because 2-(alkoxycarbonyl)cyclopentenolate anion is not isolated as ester or acid, the operation of reaction is simple and the yield is higher than that in the case with effecting isolation.
Among adipic acid diesters, adipic acid dialkyl esters are preferable. Exemplified as the alkyl groups for the above dialkyl esters are those having 4 or less carbon atoms such as Me (methyl), Et (ethyl), n-Pr (propyl), iso-Pr, n-Bu (butyl), iso-Bu, sec-Bu and tert-Bu. Two alkyl groups contained in the adipic acid dialkyl ester can be either the same or different. They have preferably the same alkyl groups of Me, Et, n-Pr or iso-Bu, more preferably they are dimethyl adipate and diethyl adipate.
As the alkoxide, M(OR)n, commercially available common ones can be used. The alkali metals and alkaline earth metals of xe2x80x9cMxe2x80x9d are exemplified by sodium, potassium, lithium, calcium and magnesium. Exemplified as xe2x80x9cRxe2x80x9d are alkyl groups having 5 or less carbon atoms such as Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl and tert-amyl. The symbol xe2x80x9cnxe2x80x9d represents the number corresponding to the valence of M, and (OR)""s of n in number can be either the same or different. Preferably, it has the same alkoxyl groups, wherein R is an alkyl group such as Me, Et, n-Pr or iso-Pr.
Exemplified as the foregoing alkoxides are lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide and magnesium methoxide; lithium ethoxide, sodium ethoxide, potassium ethoxide, calcium ethoxide and magnesium ethoxide; lithium n-propoxide, sodium n-propoxide, potassium n-propoxide, calcium n-propoxide and magnesium n-propoxide; lithium iso-propoxide, sodium iso-propoxide, potassium iso-propoxide, calcium iso-propoxide and magnesium iso-propoxide; lithium n-butoxide, sodium n-butoxide, potassium n-butoxide, calcium n-butoxide and magnesium n-butoxide; lithium iso-butoxide, sodium iso-butoxide, potassium iso-butoxide, calcium iso-butoxide and magnesium iso-butoxide; lithium sec-butoxide, sodium sec-butoxide, potassium sec-butoxide, calcium sec-butoxide and magnesium sec-butoxide; lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, calcium tert-butoxide and magnesium tert-butoxide; lithium 1-pentoxide, sodium 1-pentoxide, potassium 1-pentoxide, calcium 1-pentoxide and magnesium 1-pentoxide; lithium 2-pentoxide, sodium 2-pentoxide, potassium 2-pentoxide, calcium 2-pentoxide and magnesium 2-pentoxide; lithium 3-pentoxide sodium 3-pentoxide, potassium 3-pentoxide, calcium 3-pentoxide and magnesium 3-pentoxide; lithium tert-amyloxide, sodium tert-amyloxide, potassium tert-amyloxide, calcium tert-amyloxide and magnesium tert-amyloxide; lithium neopentoxide, sodium neopentoxide, potassium neopentoxide, calcium neopentoxide and magnesium neopentoxide; and so forth. Exemplified as particularly suitable ones are lithium methoxide, sodium methoxide and potassium methoxide, lithium ethoxide, sodium ethoxide and potassium ethoxide, lithium iso-propoxide, sodium iso-propoxide and potassium iso-propoxide, and lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide.
As for the halomethylstyrene, styrene having fluoromethyl-, chloromethyl-, bromomethyl- or iodomethyl group is used. Preferable ones are chloromethylstyrene and bromomethylstyrene. Among them, chloromethylstyrene is desirable, particularly p-chloromethylstyrene is preferable.
In the present step, reaction solvents are preferably used. The solvents can vary depending on the kinds of adipic acid diesters.
In the initial condensation reaction of adipic acid diester with alkoxide, 1 equivalent of alcohol is produced as a by-product. By means of continuous or intermittent removal of the alcohol, the reaction proceeds to produce the above-mentioned 2-(alkoxycarbonyl)cyclopentenolate anion. Therefore, the procedure for removing selectively the produced alcohol from the reaction system is inevitable for the purpose of acceleration of reaction. As the removal operation, it is convenient to distill off with heating under atmospheric pressure or reduced pressure. Therefore, when a solvent is used for the reaction, its boiling point must be the same as or higher than that of the by-product alcohol.
For example, when dimethyl adipate is used as adipic acid diester, a solvent having a boiling point higher than that of methanol (about 65xc2x0 C.) is used. The solvents are exemplified by nitrogen-containing compounds such as dimethyl formamide and acetonitrile; ether such as tetrahydrofuran; ketones such as acetone and methyl ethyl ketone; ester such as ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as octane, nonane, decane and isododecane; and the mixed solvents of them. Among them, toluene and benzene are preferable, and toluene is more preferable.
When adipic acid diester other than dimethyl adipate is used, solvents conforming to the above description can be used.
Concerning the use quantity of solvent for reaction, for example, 500 to 5,000 ml of solvent is used relative to 1 mole of adipic acid diester. The amount is preferably 800 to 3,000 ml, particularly 1,000 to 2,000 ml.
The above M(OR)n and adipic acid diester are allowed to react together, preferably in a solvent, in a temperature range of 0 to 300xc2x0 C., preferably 10 to 250xc2x0 C., more preferably 20 to 200xc2x0 C., within 24 hours, preferably for 6 hours, and more preferably for one hour.
During the reaction, the produced alcohol is distilled off under atmospheric pressure or reduced pressure. In order to remove the alcohol completely, it is preferable to remove simultaneously a part of solvent. In the case when a reaction solvent is distilled off, the solvent can be newly supplemented.
When alkoxide is reacted with adipic acid ester, the alkoxide can be used in the form of solid, for example, it is dried and preferably as fine powder, or as a solution of alkoxide in alcohol. Preferably, alcoholic solution containing dissolved alkoxide is used. The alcohol content is distilled off before the reaction with adipic acid ester starts substantially. By carrying out this procedure, suspension containing alkoxide finely dispersed in a reaction mixture is obtained, which can produce a desirable result.
As to the amount of alkoxide, for example, 0.1 to 10 equivalents of alkoxide can be used for 1 mole of adipic acid diester. When M is an alkali metal, 1 mole of alkoxide corresponds to 1 equivalent, and when M is an alkaline earth metal, 1 mole of alkoxide corresponds to 2 equivalents. It is preferable that 0.5 to 2 equivalents of alkoxide is used relative to 1 mole of adipic acid diester. It is particularly desirable that the effective amount of alkoxide is 0.7 to 1 equivalent during reaction.
When alcohol remains after the reaction, the alcohol can be distilled off.
By the above reaction of adipic acid diester with alkoxide, the above 2-(alkoxycarbonyl)cyclopentenolate anion can be obtained, the latter of which is successively subjected to coupling with halomethylstyrene without isolation. Although the by-product alcohol is distilled off in order to accelerate reaction as described above, it is not always necessary that the reaction mixture is completely free from the by-product alcohol. The reaction mixture containing a certain amount of alcohol as by-product can be fed into the next step of coupling reaction without any treatment. If unreacted substances coexist, it is rather favorable for the next coupling reaction. Therefore, the reaction mixture containing unreacted substances can be fed directly to the next coupling reaction.
Thus, halomethylstyrene is added to the obtained reaction mixture to carry out coupling reaction. The amount of halomethylstyrene is 0.1 to 20 moles, preferably 0.5 to 2 moles, more preferably 0.7 to 1.5 moles, relative to 1 mole of previously added adipic acid diester.
The temperature of reaction is in the range of 0 to 150xc2x0 C., preferably 20 to 150xc2x0 C., more preferably room temperature to 80xc2x0 C.
The time length of reaction is 24 hours or less, preferably 0.1 to 20 hours, more preferably 1 to 10 hours.
Though the coupling reaction can be carried without reaction solvent, it is also possible to use a solvent. In the like manner as the foregoing, usable solvents are exemplified by nitrogen-containing compounds such as dimethyl formamide and acetonitrile; ether such as tetrahydrofuran; acetals; ketones such as acetone and methyl ethyl ketone; ester such as ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as octane, nonane, decane and isododecane; and the mixed solvents of them. Among them, toluene and benzene are preferable, and toluene is more preferable.
As to the amount of reaction solvents, for example, 500 to 5,000 ml, preferably 800 to 3,000 ml, more preferably 1,000 to 2,000 ml, can be used relative to 1 mole of adipic acid diester that is added previously.
After the reaction, residual base is neutralized with acid, which is followed by extraction and water washing, and then extraction solvent is removed. When the reaction solvent is water soluble one, it is removed under reduced pressure. After that, an extraction solvent is added and extraction and water washing are carried out, and further, the extraction solvent is removed. As the extraction solvents, appropriate ones can be used, while toluene is usually employed. It is not always necessary to remove completely the extraction solvents remaining after extraction, as long as they do not have influence on the next step. They can be used as dilution solvents in the next step (1-2).
Compound I can be obtained according to the above method, and it is used in the next step (1-2). Compound I can be supplied to step (1-2) after refined further by methods of distillation or others, but additional refining is not necessary.
In the obtained product, the compound as represented by the formula V (hereinafter referred to as xe2x80x9ccompound Vxe2x80x9d) is sometimes present in a small amount. However, it is converted finally into the intended compound III, therefore its mixing does not cause any trouble. 
Halomethylstyrene used in step (1-1) is liable to polymerize by itself. The polymerization is further accelerated particularly when it is handled in a heated and pressurized system. Therefore, when halomethylstyrene is directly subjected to carbonylation, it is necessary to dilute the reaction system with a large amount of solvent as mentioned above, which is industrially costly. However, a compound I, which is obtained by coupling halomethylstyrene with cyclopentanone carboxylic acid ester, is difficult to polymerize by itself. As shown by the examples of the present invention, the dilution solvent required in carbonylation of compound I is only several times or less the amount of substrate.
Further, in the method of the present invention, the amount of by-product resulting from the polymerization of halomethylstyrene is small, which is favorable also from the viewpoint of waste disposal. Accordingly, the present invention is superior by far in efficiency to the conventional method comprising (i) carbonylation of p-chloromethylstyrene, (ii) coupling with cyclopentanone carboxylic acid ester, and (iii) decarboxylation and hydrolysis. Step (1-2): [Carbonylation]
In the present step (1-2), the compound I resulting from the above step (1-1) is caused to react with carbon monoxide and water or alcohol, in the presence of catalyst and dilution solvents, or with addition of polymerization inhibitor if necessary, to obtain a compound II. The catalysts used in the present step is any selected from the group of (i) metal complex itself, (ii) substance comprising metal complex and ligand, and (iii) substance comprising metal complex, ligand and additive.
When a catalyst corresponding to (ii) or (iii) is used, it is desirable to use the procedure for developing catalyst activity by mixing metal complex, or metal complex and additive, with alcohol to be used in the reaction, then adding ligand.
As metal complexes, transition metal complexes, preferably complexes of transition metal of group VIII, more preferably those of cobalt, rhodium, platinum and palladium can be used. As the examples, there are Co2(CO)8, RhCl(PPh3)3, wherein xe2x80x9cPhxe2x80x9d represents phenyl group, RhCl(CO)(PPh3)2, H2PtCl6, Pd carbon, Pd black, Pd(PPh3)4, Pd(PPhBu2)2, Pd(P Bu3)2, Pd(P(OPh)3)4, Pd(P(OEt)3)4, Pd(C2H4)(PPh3)2, Pd(PhCN)2(BF4)2, Pd(MeCN)4(BF4)2, Pd(PhCN)2(PPh3)2(BF4)2, Pd(MeCN)2(PPh3)2(BF4)2, Pd(acac)2, wherein xe2x80x9cacacxe2x80x9d represents acetylacetonato group, Pd2(dba)3CHCl3, Pd(dba)2, wherein xe2x80x9cdbaxe2x80x9d represents dibenzylideneacetone, PdO, PdS, Pd(NO3)2, PdSO4, PdX2, wherein xe2x80x9cXxe2x80x9d represents Cl, Br, I, OCOCF3 or OCOMe, PdX2(PhCN)2, PdX2(MeCN)2, PdX2(CO)2, wherein xe2x80x9cXxe2x80x9d represents Cl, Br, or I, Pd(COD)2, PdX2(COD)2, wherein xe2x80x9cXxe2x80x9d represents Cl, Br or I and xe2x80x9cCODxe2x80x9d represents 1,5-cyclo-octadiene, Pd(MA)(PPh3)2, wherein xe2x80x9cMAxe2x80x9d represents maleic anhydride, M2PdX4, wherein xe2x80x9cXxe2x80x9d represents Cl, Br, I or OCOMe and xe2x80x9cMxe2x80x9d represents H, NH4, Li, Na or K, PdX2(PArArxe2x80x2Arxe2x80x3)2, wherein xe2x80x9cXxe2x80x9d represents Cl, Br or I and Ar, Arxe2x80x2 or Arxe2x80x3 represents the same or different aryl group, PdX2(PPh3)2, PdX2(PRPh2)2, PdX2(PR2Ph)2, PdX2(PR3)2, Pd2X4(PR3)2, wherein xe2x80x9cXxe2x80x9d represents Cl, Br or I and xe2x80x9cRxe2x80x9d represents Me, Et, Pr, Bu, OPh, menthyl group or cyclohexyl group, PdX2(dppf), wherein xe2x80x9cXxe2x80x9d represents Cl, Br or I and xe2x80x9cdppfxe2x80x9d represents bis(diphenylphosphino)ferrocene, PdX2(Ph2P(CH2)nPPh2), wherein xe2x80x9cXxe2x80x9d represents Cl, Br or I and xe2x80x9cnxe2x80x9d represents an integer from 1 to 4, PdR2(PRxe2x80x23)2, wherein R and Rxe2x80x2 represents Me, Et, Pr, Bu, OPh or Ph, PdXR(PRxe2x80x23)2, wherein xe2x80x9cXxe2x80x9d represents Cl, Br or I, xe2x80x9cRxe2x80x9d represents H, Me, Et, Pr, Bu, Ph, CH2Ph or COMe and Rxe2x80x2 represents Me, Et, Pr, Bu, OPh, Ph or cyclohexyl group, [Pd(xcex73-CH2CHCH2)X]2, [Pd(xcex73-CH2CHCH2)X(PPh3)], [Pd(xcex73-CH2CHCHCH2X)X]2, wherein xe2x80x9cXxe2x80x9d represents Cl, Br or I, Pd(xcex73-CH2CHCH2)2, Pd(xcex73-CH2CHCH2)(xcex75-C5H5) and so forth, but the metal complexes used in the present step are not limited to these.
The amounts of metal complex is 1 mole or less relative to 1 mole of compound I, preferably in the range of 0.00001 to 0.1 mole, more preferably 0.0001 to 0.01 mole.
Ligands are compounds that have the property to produce coordination compounds, and phosphines or phosphites are favorably used, and more favorably triarylphosphines. As the examples, there are PPh3, PArArxe2x80x2Arxe2x80x3 (Ar, Arxe2x80x2 and Arxe2x80x3 are the same or different aryl groups), PRPh2, PR2Ph, PR3, wherein xe2x80x9cRxe2x80x9d represents Me, Et, n-Pr, iso-Pr, n-Bu, menthyl group or cyclohexyl group, Ph2P(CH2)nPPh2, wherein xe2x80x9cnxe2x80x9d represents an integer from 1 to 4, bis(diphenylphosphino)ferrocene, P(OPh)3 and so forth, but the ligands used in the present step are not limited to these.
The amount of ligand is 10 equivalent or less relative to 1 equivalent of metal complex, preferably 5 equivalent or less, more preferably 2 to 4 equivalent.
As additives, inorganic substances are used, preferably tin chloride, copper oxide, and alkali metal salts or alkaline earth metal salts. Among them, alkali metal salts are favorable. As the examples, there are SnCl2, CuCl2, MgCl2, CaCl2, NaCl, NaBr, LiCl, LiBr, KCl, KBr and so forth, but the additives used in the present step are not limited to these.
The additive can be Brxcfx86nsted acid and Lewis acid depending on the metal complexes to be used. As Brxcfx86nsted acids, it is preferable to use the ones, which counter anions coordinate weakly or do not coordinate at all with metal atoms. As the examples, there are p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, HBF4, HBAr4, wherein xe2x80x9cArxe2x80x9d represents aryl group, HPF6 and so forth, but Brxcfx86nsted acids used in the present step are not limited to these. From the viewpoint of easy handling, p-toluenesulfonic acid is particularly favorable.
As Lewis acids, general compounds can be used, preferably those comprising B, Al, Ti, Zn, Sn, Sb and so forth. Among them, those comprising B, Al or Ti are favorable. As substances to be connected with these elements, there are alkoxyl group, halogen atom, oxygen atom, hydrogen atom and so forth. Among theme, halogen is favorable. As the examples of Lewis acids, there are TiX4, BX3, AlX3, ZnX2, SnX4, SbX5, wherein xe2x80x9cXxe2x80x9d represents halogen atom, Ti(OR)nX4xe2x88x92n, wherein xe2x80x9cRxe2x80x9d represents methyl group, ethyl group, isopropyl group or butyl group, xe2x80x9cXxe2x80x9d represents halogen atom, and xe2x80x9cnxe2x80x9d represents an integer from 1 to 4, TiHnCl4xe2x88x92n, wherein xe2x80x9cnxe2x80x9d represents an integer from 1 to 3, Al(OR)3, Zn(OR)2, wherein xe2x80x9cRxe2x80x9d represents methyl group, ethyl group or isopropyl group, TiO2, Al2O3, ZnO2, SnO2, SbO5 and so forth, but Lewis acids used in the present step are not limited to these.
These Lewis acids in themselves are difficult to handle. Therefore, it is preferable to use them in the form of complexes containing water, ether, alcohol, ester, carboxylic acid or THF (tetrahydrofuran) as ligand. As the examples, there are BF3xe2x80x94OEt2, BF3xe2x80x94OH2, BF3xe2x80x94(THF)2, TiCl4xe2x80x94(THF)2, AlCl3xe2x80x94(H2O)n and so forth.
The amount of additive is 20 equivalents or less relative to 1 equivalent of metal complex, preferably 0.1 to 10 equivalents, more preferably 1 to 4 equivalents.
As dilution solvents, commonly available organic solvents can be used. As the examples, there are benzene, toluene, xylene, tetrahydrofuran, acetone, methyl ethyl ketone, ethyl acetate and so forth, but the dilution solvents used in the present step are not limited to these.
As to the amount of dilution solvent, solvent is 20 times or less the volume of compound I, preferably 10 times or less, more preferably 0.5 to 3 times.
As polymerization inhibitors, it is possible to use the compounds that do not hinder carbonylation and reactions thereafter. As the examples, there are nitromethane, nitrobenzene, hydroquinone, CuCl2, FeCl2, 4-tert-butylcatechol, nitrophenol, nitrocresol, 2,6-di-tert-butyl-4-methylphenol, 4-methoxyphenol and so forth, but the polymerization inhibitors used in the present step are not limited particularly. Any mixture comprising two or more kinds of polymerization inhibitors may be used.
The amount of polymerization inhibitor is 10% or less relative to the mass of compound I, preferably 1% or less, more preferably 0.1% or less.
As carbon monoxide, the one having the purity of 20% or more, preferably 50% or more, more preferably 80% or more is used.
Carbon monoxide is prepared in such an amount that 1 mole or more can be supplied to 1 mole of compound I. When hydrogen is present together with carbon monoxide, the partial pressure of carbon monoxide is reduced depending on the amount of coexisting hydrogen. That affects the reaction of the present step somewhat, but the reaction proceeds without any trouble.
Exemplified as alcohols are methyl alcohol, ethyl alcohol, n-propyl alcohol, iso-propyl alcohol, n-butyl alcohol, sec-butyl alcohol, tert-butyl alcohol and iso-butyl alcohol. Methyl alcohol, ethyl alcohol, n-propyl alcohol and iso-propyl alcohol are preferably used, and particularly methyl alcohol and ethyl alcohol are favorable.
The amount of alcohol is 1 mole or more relative to 1 mole of compound I, preferably 1 to 30 moles, more preferably 1 to 3 moles.
An autoclave is charged with the above catalyst, a compound I, water or alcohol, and dilution solvent. Then, at the reaction temperature of 40 to 200xc2x0 C., preferably 50 to 140xc2x0 C., more preferably 70 to 100xc2x0 C., carbon monoxide is pressurized to 0.1 to 30 MPa, preferably 0.2 to 10 MPa, more preferably 2.5 to 7 MPa, and stirring is carried out for 0.1 to 100 hours, preferably 6 to 30 hours, more preferably 8 to 24 hours.
Otherwise, it is also possible to mix catalyst, alcohol and dilution solvent in an autoclave, and then add a compound I successively into the reaction system under the above conditions. In this case, it is preferable to supply a compound I over 0.1 to 100 hours, preferably for 5 to 20 hours, more preferably for 7 to 20 hours.
After the reaction is over, carbon monoxide is removed and the condition is set at normal temperature and pressure. When catalysts are precipitated in a reaction mixture, they can be recovered by filtration and reused. After appropriate filtration of catalysts, separation by distillation can be carried out under reduced pressure to obtain a compound II in high purity. The meta-isomer and para-isomer of compound II have different boiling points, therefore it is possible to separate the mixture of them by rectification. By this method, the pare-isomer can be obtained as a precursor of loxoprofen in high purity.
In the carbonylation carried out in the present step, the temperature is relatively high, and moreover metal catalysts are present. However, a specific substituent group is substituted for halomethyl group of halomethylstyrene such as chloromethyl group of chloromethylstyrene, therefore the polymerization activity of vinyl group is suppressed, so that the reaction of high efficiency can be accomplished.
In the present carbonylation, the compound as represented by the general formula VI (hereinafter referred to as xe2x80x9ccompound VIxe2x80x9d) is produced as an isomer of compound II in a small amount, 
wherein Rxe2x80x2 represents an alkyl group having 4 or less carbon atoms, and Rxe2x80x3 represents hydrogen atom or an alkyl group having 4 or less carbon atoms.
Further, the compound as represented by the general formula VII resulting from carbonylation of compound V is produced in a trace, 
wherein Rxe2x80x3 represents hydrogen atom or an alkyl group having 4 or less carbon atoms.
However, they are converted finally into the intended compound III, therefore their mixing does not cause any trouble. Step (1-3): [Decarboxylation and Hydrolysis]
In the present step, for example, according to the method of the above International Publication, hydrolysis and decarboxylation are carried out using acids such as sulfuric acid and hydrochloric acid.
Otherwise, it is possible to obtain a compound III by heating the compound II obtained in the above step (1-2) together with water and acid in the presence of solvent so as to carry out decarboxylation and hydrolysis step by step. In the present step of decarboxylation and hydrolysis, although the compound II has two ester groups, both groups can be treated at the same time, which is advantageous. The ester group of compound I can be subjected to decarboxylation and hydrolysis before carbonylation of the step (1-2). However, with the hydrolysis and decarboxylation according to the present step, it is possible to treat two ester groups at the same time, even if a compound has two ester groups like compound II.
As acids, commonly available mineral acids can be used. As the examples, there are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and so forth, but the acids used in the present step are not limited to these.
The amount of acids is 20 times or less the mass of compound II, preferably 0.001 to 10 times, more preferably 0.001 to 5 times.
As solvents, hydrophilic organic solvents are preferable. When the reaction is carried out in the presence of hydrophilic organic solvent, the time of reaction can be shortened preferably. Exemplified as hydrophilic organic solvents are tetrahydrofuran, ethyl acetate, acetonitrile, acetic acid and so forth, but the solvents used in the present step are not limited to these. Acetic acid is particularly favorable.
Hydrophilic organic solvents are used in the amount of 20 times or less the mass of compound II, preferably 0.5 to 10 times, more preferably 1 to 5 times.
A reaction vessel is charged with the above acid, solvent and a compound II. Then, at room temperature to 150xc2x0 C., preferably 50xc2x0 C. to 120xc2x0 C., more preferably 90xc2x0 C. to 110xc2x0 C., stirring is carried out for 1 to 100 hours, preferably 2 to 24 hours, more preferably 6 to 12 hours. The time of reaction is shortened by removing alcohol produced as by-product from the reaction zone with Dean-Stark apparatus or the like.
After the reaction, extraction is carried out with a hydrophilic organic solvent such as toluene and the solvent is removed to obtain a raw product of compound III. Further, recrystallization can be carried out using good solvent such as ether and bad solvent such as hexane to obtain a compound III in high purity.
In the following, the process for production comprising the steps (2-1) and (2-2) will be described in serial order of the steps.
Step (2-1): [Coupling]
In step (2-1), after the reaction of dimethyl adipate with the above alkoxide M(OR)n is carried out to produce 2-(alkoxycarbonyl)cyclopentenolate anion, the obtained product is successively subjected to coupling with a compound IV to obtain a compound II.
In the present step, 2-(alkoxycarbonyl)cyclopentenolate anion obtained as an intermediate product, its ester, the corresponding acid and the like, without isolation, can be successively subjected to reaction with a compound IV. Therefore, the operation of reaction is simple, and the yield is higher than in the case with isolation.
As above, it is important to cause 2-(alkoxycarbonyl)cyclopentenolate anion to react with a compound IV without isolation. As long as isolation is excluded, the other simple refining is allowed. In the reaction of alkoxide M(OR)n, as base and adipic acid diester, if only excess of base is avoided, there is no need for apprehension that the base might react with a compound IV as a side reaction.
Adipic acid diester and alkoxide M(OR)n used in step (2-1) are the same as those described in the above-mentioned step (1-1).
Exemplified as compound IV of 2-(halomethylphenyl)propionic acids or their esters are 2-(fluoromethylphenyl)propionic acid or its ester, 2-(chloromethylphenyl)propionic acid or its ester, 2-(bromomethylphenyl)propionic acid or its ester, and 2-(iodomethylphenyl)propionic acid or its ester. Preferable ones are 2-(chloromethylphenyl)propionic acid, methyl 2-(chloromethylphenyl)propionate, ethyl 2-(chloromethylphenyl)propionate, 2-(bromomethylphenyl)propionic acid, methyl 2-(bromomethylphenyl)propionate and ethyl 2-(bromomethylphenyl)propionate. Among them, methyl 2-(chloromethylphenyl)propionate, ethyl 2-(chloromethylphenyl)propionate, methyl 2-(bromomethylphenyl)propionate and ethyl 2-(bromomethylphenyl)propionate are favorable. Further, methyl 2-(p-chloromethylphenyl)propionate, ethyl 2-(p-chloromethylphenyl)propionate, methyl 2-(p-bromomethylphenyl)propionate and ethyl 2-(p-bromomethylphenyl)propionate are particularly favorable. These acids and esters, especially acids are commercially available at a low price.
When 2-(halomethylphenyl)propionic acid is caused to react with lower alcohol using acid catalyst, it can be easily converted into 2-(halomethylphenyl)propionic acid ester. Accordingly, raw products of the above reaction containing these esters can be used for coupling advantageously.
In the present step, reaction solvents are used preferably. The kinds and the amount of solvent in the condensation reaction of adipic acid diester and alkoxide are the same as those in the above step (1-1).
Further, various conditions in the reaction of adipic acid diester and alkoxide are also the same as those in the above step (1-1). When alcohol remains after the reaction, the alcohol can be distilled off later.
By the above reaction of adipic acid diester with alkoxide, the above 2-(alkoxycarbonyl)cyclopentenolate anion can be obtained, the latter of which is successively subjected to coupling with a compound IV without isolation.
In this case, the by-product of alcohol is distilled off from the viewpoint of accelerating reaction as above-mentioned. However, the reaction mixture does not need to be completely free from by-product of alcohol. The reaction mixture containing a certain amount of alcohol as by-product can be fed into the next step of coupling reaction without any treatment. The reaction mixture containing unreacted substances can also be fed directly to the coupling reaction.
Thus, a compound IV is added to the obtained reaction mixture to carry out coupling reaction. The amount of compound IV is 0.1 to 20 moles relative to 1 mole of adipic acid diester added previously, preferably 0.5 to 2 moles, more preferably 0.7 to 1.5 moles.
The temperature of reaction is in the range of 0 to 150xc2x0 C., preferably 20 to 150xc2x0 C., more preferably room temperature to 80xc2x0 C.
The time of reaction is 24 hours or less, preferably 0.1 to 20 hours, more preferably 1 to 10 hours.
Although coupling reaction can be carried out without reaction solvent, solvents may be used. As to the solvents, the kinds and the amount can be determined in the same way as in the case of the coupling reaction of the above step (1-1).
After the reaction, residual base is neutralized with acid, extraction and water washing are carried out, and then extraction solvent is removed. When reaction solvent is water soluble, the solvent is removed under reduced pressure. Then, extraction solvent is added, extraction and water washing are carried out, and extraction solvent is removed. It is not necessary to remove completely the extraction solvents remaining after extraction, as long as they do not influence the next step.
Compound II can be obtained according to the above method, and it is used in the next step (2-2). Compound II can be refined further by methods such as distillation and then supplied to step (2-2), but the additional refining is not necessary.
In the obtained product, the compound as represented by the formula VII is sometimes present in a trace. However, it is converted finally into the intended compound III, therefore its mixing does not cause any trouble. 
wherein
Rxe2x80x3 is hydrogen atom or an alkyl group having 4 or less carbon atoms, Step (2-2): [Carbonylation and Hydrolysis]
The present step can be carried out in the same way as the above-mentioned step (1-3). That is, acid catalysts, solvents and reaction conditions are all the same as those of the above.